The Molecular Biology and Human Genetics Program analyzes the genomic information from studies of organisrns from yeast to humans in, the discovery and functional analysis of novel genes responsible for cancer predisposition in high risk families as well as in sporadic cancers. Cancer development is associated with a series of changes in cellular genes. These changes occur as mutations or variations in gene expression in cancer causing genes and in other genes, which respond to them. Genetic alterations provide molecular signatures specific to each tumor type. Cancer susceptibility genes frequently cause so-called "genomic instability" in which cells develop DNA damage in critical cancer-causing genes such as oncogenes and tumor suppressor genes. Either germline or somatic mutations affect proteins involved in signal transduction such as growth factor receptor pathways or transcription factors leading to changes in gene expression. Similarly, epigenetic changes can occur in the germ line or in somatic cells. Studies in human populations at extreme risk to cancer can be applied to the general population in which the genetics of cancer risk is subtler. The current efforts of this Program are on mechanisms of genomic instability, chromatin structure, cell cycle checkpoint control, transcriptional regulation of signal transduction, and post-translational control mechanisms. We utilize cell lines and whole animals to model the genetic mechanisms leading to precancerous cells, the molecular signatures of precancerous lesions, and the critical genetic events in the progression of these cells to neoplasia. Because of the extensive body of genetic information on DNA repair genes and growth control mechanisms in model organisms, we are applying the genetics of yeast and mouse model systems to understand human gone structure and function. We are analyzing the human homologues of well-characterized DNA repair and checkpoint genes for their role in genetic and sporadic human cancers. These genetic mechanisms will provide useful molecular targets for early detection, chemoprevention and chemotherapy. This body of knowledge also provides a novel approach to cancer risk determination in special populations.